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The d-leucine amino acid residue necessary for the synthesis of BMS-561392, 1, was employed as a chiral directing group for a diastereoselective enolate amination to establish the quaternary chiral center. Enhanced diastereomeric ratios were observed while conducting the enolate amination with 1-chloro-1-nitrosocyclopentane 6 in the presence of LiCl. Analogies are drawn between known tertiary amide amino alcohol chiral auxiliaries which have been used to effect diastereoselective enolate alkylations and aminations. Once the stereochemical features of 1 were established, an efficient reaction sequence was devised to complete its synthesis. During the course of this research, accelerated reaction calorimetry (ARC) data substantiated that the aminating agent 1-chloro-1-nitrosocyclopentane 6 was not safe to use as a neat compound. Consequently, a preparation and use of 6 as a stock solution in methyl tert-butyl ether (MTBE) was developed that rendered it safe for use.

D-D4FC ( 1 ) is an anti-HIV agent currently under phase II clinical trial (Pharmaset Inc). Its molecular architecture is suitable for a Ferrier rearrangement kind of operation on a furanoid glycal to fix the position of the double bond and the relative stereochemistry. Despite the fact that classical Ferrier rearrangement does not work on furanoid glycals, a palladium mediated modified protocol has been developed for the glycosidation of an aromatization prone xylo-furanoid glycal ( 5 ) for the synthesis of D-D4FC.

Additional information is presented for the transformation of a kinetic resolution into a dynamic kinetic resolution of the isobutyl ester 5b to form the acid 2 in high yield and ee via the intermediacy of a thioester 6c, (Pesti, J. A.; Yin, J.; Zhang, L.-H; Anzalone, L. J. Am. Chem. Soc. 2001, 123, 11075−11076.). The development of optimized reaction conditions for the preparation of 6c, its dynamic kinetic resolution to 2, and the scale-up of both reactions into a pilot plant are described.

The synthesis of efavirenz (DMP 266) involves a highly enantioselective asymmetric reaction of ketone 2a with lithium cyclopropylacetylide 3a in the presence of (1R,2S)-pyrrolidinylnorephedrine (PN...

Anti-HIV agent β-F-ddA (1) has been synthesized starting from readily available non-sugar, (S)-(+)-Dihydro-5-(hydroxymethyl)-2-(3H)-furanone (4). A highly syn-stereoselective fluorination of the hydroxy lactone 2 generates the key intermediate fluorolactone 5 in a short and concise synthetic sequence. Reduction of 5 followed by bromination generates the aglycon which is glycosylated to generate F-ddA by amination and deprotection. Steric bulk of the 5-protecting group has minimal effect on the steric course of glycosylation.

Unlike Congress, the American Chemical Society Board of Directors has term limits. It has been my honor and great privilege to serve our society on the board for nine years, the past three as board chair. “End of watch” is a phrase often used by the military and law enforcement to indicate the completion of a shift or retirement from active duty. My watch began in 2007 just when the financial markets were on the verge of collapse and the Great Recession was about to commence. Working closely with ACS management, the board of directors had to take immediate action guided by the ACS finance department. Those were difficult days that required hard choices such as freezing the defined contribution retirement plan, capping the society’s financial contributions to the retiree medical plan, calling for a hiring freeze along with a workforce reduction, and eliminating open requisitions for new hires. Without

Afoxolaner is an isoxazoline compound characterized by a good safety profile and extended effectiveness against fleas and ticks on dogs following a single oral administration. In vitro membrane feeding assay data and in vivo pharmacokinetic studies in dogs established an afoxolaner blood concentration of 0.1–0.2 μg/ml to be effective against both fleas ( Ctenocephalides felis ) and ticks ( Dermacentor variabilis ). Pharmacokinetic profiles in dogs following a 2.5 mg/kg oral dosage demonstrated uniform and predictable afoxolaner plasma concentrations above threshold levels required for efficacy for more than one month. Dose ranging and a 5-month multi-dose experimental study in dogs, established that the 2.5 mg/kg oral dosage was highly effective against fleas and ticks, and produced predictable and reproducible pharmacokinetics following repeated dosing. Mode of action studies showed that afoxolaner blocked native and expressed insect GABA-gated chloride channels with nanomolar potency. Afoxolaner has comparable potency between wild type channels and channels possessing the A302S (resistance-to-dieldrin) mutation. Lack of cyclodiene cross-resistance for afoxolaner was confirmed in comparative Drosophila toxicity studies, and it is concluded that afoxolaner blocked GABA-gated chloride channels via a site distinct from the cyclodienes.

This report describes a new convergent, selective, and economical synthesis of DMP 777,1 ending with the coupling of the chiral β-lactam half of the molecule (1) to the chiral amine as the isocyanate (2). Other steps involve the coupling of the β-lactam 3 to the phenolic moiety under phase-transfer conditions, followed by resolution of the resulting piperazine derivative using a chiral acid, and recycling of the undesired enantiomer also under phase-transfer conditions. The chiral amine 4 was produced efficiently starting from (R)-α-methylbenzylamine and the corresponding butyrophenone.

A practical and scaleable synthetic procedure for the deprotection of a p-methoxy benzyl group from the tertiary carbinol 2 in the commercial synthesis of SUSTIVA® (efavirenz) 1 is described. The methodology involves a two step, one pot operation with an isolated yield of 82.5% with a product purity of > 99.5%.

OBJECTIVE To define the affinity and specificity of SJ874, a nonpeptide antiplatelet agent for platelet glycoprotein Ilb/IIIa integrin, and to determine the antiplatelet efficacy of SJ874 relative to those of glycoprotein IIbIIIa antagonists and aspirin. METHODS Binding affinity and specificity of SJ874 for platelet glycoprotein IIb/IIIa integrin were determined using integrin-mediated binding and adhesion assays with human cells. Additionally, the antiplatelet efficacy of SJ874 was determined and compared with those of other glycoprotein IIb/IIIa antagonists and aspirin using light-transmittance and laser-scattering aggregometry. RESULTS SJ874 inhibited aggregation of human platelets induced by 10 micromol/l adenosine diphosphate (ADP) with a concentration for half-maximal effect of 0.046 +/- 0.005 micromol/l using light-transmittance aggregometry. Using laser-scattering aggregometry, SJ874 was found to totally inhibit formation both of micro-aggregates and of macro-aggregates induced either by ADP or by epinephrine. In contrast, administration of 325 mg aspirin to normal healthy volunteers attenuated formation of macro-aggregates but not micro-aggregates. SJ874 inhibited binding of [125I]-fibrinogen to activated (by ADP, epinephrine, and arachidonic acid at concentrations of 100 micromol/l each) gel-filtered human platelets with a concentration for half-maximal effect of 0.0012 +/- 0.0005 micromol/l. SJ874 was demonstrated to associate more tightly with resting human platelets than did DMP754 [1] and slightly less tightly than did DMP802 [2]. SJ874 was demonstrated to exhibit a high degree of specificity for platelet glycoprotein IIb/IIIa (alphaIIb/beta3) integrin compared with other known integrins, including alphavbeta3, alphavbeta5, and alpha5beta1 (concentration for half-maximal effect > 100 micromol/l). CONCLUSION SJ874 is a potent and specific platelet glycoprotein IIb/IIIa antagonist with high affinity for and tight association with human platelets. These data suggest that SJ874 might have good antiplatelet utility for inhibiting formation both of platelet micro-aggregates and of macro-aggregates of platelets and a long duration of action in humans due to its slow dissociation from human platelets.

Allyltrichlorosilane can add to α-oxocarboxylic acids in the presence of DMF and HMPA. The α-carboxylic substituent exerts a remarkable neighboring group effect on the reaction. The reaction presumably proceeds in an intramolecular fashion through a ‘rigid’ bicyclic transition state assembly involving a hypervalent silicate species, which produces the chemoselectivity approaching 100%.

The asymmetric synthesis of the HIV non-nucleoside reverse transcriptase inhibitor (NNRTI) DPC 961 is achieved in three steps with an overall yield of >55%. The asymmetry is induced by the chiral auxiliary (R)-(+)-α-methylbenzylamine, utilizing a new asymmetric 1,4-addition protocol.

A highly enantioselective and practical synthesis of the HIV-1 reverse transcriptase inhibitor efavirenz (1) is described. The synthesis proceeds in 62% overall yield in seven steps from 4-chloroaniline (6) to give efavirenz (1) in excellent chemical and optical purity. A novel, enantioselective addition of Li-cyclopropyl acetylide (4a) to p-methoxybenzyl-protected ketoaniline 3a mediated by (1R,2S)-N-pyrrolidinylnorephedrine lithium alkoxide (5a) establishes the stereogenic center in the target with a remarkable level of stereocontrol.

Unsymmetric cyclic urea diols of general structure 1 can be prepared either via an isourea derived from the symmetric diamine 2 or by the selective removal of a benzyl group from certain symmetric cyclic ureas 8, employing dissolving metal reduction.

A series of lipophilic Nα-amido-neurotensin(9–13) analogs was prepared. These acylated pentapeptides exhibited good neurotensin receptor binding, as well as in vivo analgesic activity via i.c.v. and even intravenous routes of administration.

A highly efficient synthesis of (2R,3S,5S)-2-acetoxy-3-fluoro-5-(p-toluoyloxymethyl)tetrahydrofuran ( 2a ) was developed. As a key intermediate, 2a was effectively applied to the synthesis of 9-(2,3-dideoxy-2-fluoro-β- d -threo-pentofuranosyl)adenine (FddA), thus, providing a practical synthetic approach to FddA.

Microreactor technology holds great promise for simplifying process chemistry. The design of microreactors inherently simplifies heat transfer and flow. Continuous processing on a commercial scale is also achievable using these reactors, providing significant improvements in efficiency compared with batch processing. Two-phase reactions with liquid-gas and liquid-solid phases present difficulties for microreactor-based processing; however, advances in reactor design are providing some solutions to such challenges. The potential efficiencies provided by microreactors suggest that this technology will be adopted increasingly for widespread commercial applications, particularly following greater investment by companies and further improvements in engineering.

Unsymmetric cyclic urea diols of general structure 1 can be prepared either via an isourea derived from the symmetric diamine 2 or by the selective removal of a benzyl group from certain symmetric cyclic ureas 8, employing dissolving metal reduction.

A series of isoxazolidines has been synthesized as mimetics of the RGD sequence and was evaluated as antagonists of the platelet glycoprotein IIb/IIIa receptor. These compounds were shown to be highly potent GPIIb/IIIa antagonists, exhibiting submicromolar potencies.

We have discovered an efficient cyanation of aryl chlorides which employs Pd 2 (dba) 3 , dppf and Zn as the catalyst and Zn(CN) 2 as the cyanide source. Both electron-deficient and electron-rich aryl chlorides are effectively cyanated under these conditions. This discovery represents the first successful palladium-catalyzed cyanation of both electron-deficient and electron-rich aryl chlorides.

The asymmetric synthesis of the HIV non-nucleoside reverse transcriptase inhibitor (NNRTI) DPC 961 is achieved in three steps with an overall yield of >55%. The asymmetry is induced by the chiral auxiliary (R)-(+)-α-methylbenzylamine, utilizing a new asymmetric 1,4-addition protocol.

A practical approach for the conversion of aldehydes to vinyl dichlorides has been developed. These are three-step, one-pot reactions involving the formation of trichlorocarbinol by treatment of aldehydes with trichloroacetic acid and sodium trichloroacetate followed by in situ protection and elimination reactions to form the desired vinyl dichlorides in 85 to 95% yields.

The beta-amino alcohol 4 beta-morpholinocaran-3 alpha-ol is prepared by addition of morpholine to alpha-3,4-epoxycarane utilizing anhydrous magnesium bromide as Lewis acid promoter. The enantiopure amino alcohol is uniquely effective as a chiral moderator for the addition of lithium cyclopropylacetylide to an unprotected N-acylketimine. This reaction provides an efficient route to the second generation NNRTI drug candidate DPC 963.

A practical approach for the conversion of aldehydes to vinyl dichlorides has been developed. These are three-step, one-pot reactions involving the formation of trichlorocarbinol by treatment of aldehydes with trichloroacetic acid and sodium trichloroacetate followed by in situ protection and elimination reactions to form the desired vinyl dichlorides in 85 to 95% yields.

We have discovered an efficient cyanation of aryl chlorides which employs Pd 2 (dba) 3 , dppf and Zn as the catalyst and Zn(CN) 2 as the cyanide source. Both electron-deficient and electron-rich aryl chlorides are effectively cyanated under these conditions. This discovery represents the first successful palladium-catalyzed cyanation of both electron-deficient and electron-rich aryl chlorides.

A model study designed for the synthesis of the discorhabdin alkaloids is presented. The key reaction is the intramolecular para-phenolate alkylation of the mesyloxy aminonaphthoquinone 10 to afford the target tetracyclic system 11.

The 1,2-addition of lithium phenylacetylide (PhCCLi) to quinazolinones was investigated using a combination of structural and rate studies. (6)Li, (13)C, and (19)F NMR spectroscopies show that deprotonation of quinazolinones and phenylacetylene in THF/pentane solutions with lithium hexamethyldisilazide affords a mixture of lithium quinazolinide/PhCCLi mixed dimer and mixed tetramer along with PhCCLi dimer. Although the mixed tetramer dominates at high mixed aggregate concentrations and low temperatures used for the structural studies, the mixed dimer is the dominant form at the low total mixed aggregate concentrations, high THF concentrations, and ambient temperatures used to investigate the 1,2-addition. Monitoring the reaction rates using (19)F NMR spectroscopy revealed a first-order dependence on mixed dimer, a zeroth-order dependence on THF, and a half-order dependence on the PhCCLi concentration. The rate law is consistent with the addition of a disolvated PhCCLi monomer to the mixed dimer. Investigation of the 1,2-addition of PhCCLi to an O-protected quinazolinone implicates reaction via trisolvated PhCCLi monomers.

Isoxazolidines have been synthesized in diastereomeric excess up to 94% via a MgBr2-induced chelation-controlled 1,3-dipolar cycloaddition reaction with N-hydroxyphenylglycinol as a chiral auxiliary. The diastereomerically pure isoxazolidines were further transformed into cyclic and acyclic beta-amino acid derivatives.

The practical and highly diastereoselective syntheses of CF3-substituted dihydroquinazolinones via 1,4-additions of nucleophiles to chiral auxiliary substituted 2(3H)-quinazolinones is described. This methodology is applied to the syntheses of the NNRTIs (nonnucleoside reverse transcriptase inhibitors) DPC 961 (1) and DPC 083 (2), which are useful for the treatment of HIV (human immunodeficiency virus). The synthesis of DPC 961 (1) requires three steps, proceeds in >55% overall yield from the keto-aniline 9, and gives synthetic access to DPC 083 (2). In addition, the scope of the new diastereoselective 1,4-addition chemistry is investigated. The first preparation of DPC 961 (1) described in this paper is a derivatization fractional crystallization protocol.

OVER THE PAST two years, the American Chemical Society, its members, customers, and the larger chemistry enterprise have been gradually emerging from the Great Recession. The subsequent economic recovery has been slow by historic standards. Job growth has been extremely disappointing and unemployment remains at historically high levels. And as the recent congressional debate on the nation’s debt ceiling and deficit has shown, there are no simple or easy answers to our current fiscal problems, only difficult choices. What has become clear is our nation’s recovery from the recession will be measured in years, not quarters. Given this challenging economic backdrop, one could reasonably ask, “How can the American Chemical Society ensure its financial sustainability and growth?” Beginning in the early 1970s, ACS has routinely undertaken periodic assessments of the society’s financial condition and nearterm growth prospects. The assessments have typically occurred at financial planning conferences with active p...

The beta-amino alcohol 4 beta-morpholinocaran-3 alpha-ol is prepared by addition of morpholine to alpha-3,4-epoxycarane utilizing anhydrous magnesium bromide as Lewis acid promoter. The enantiopure amino alcohol is uniquely effective as a chiral moderator for the addition of lithium cyclopropylacetylide to an unprotected N-acylketimine. This reaction provides an efficient route to the second generation NNRTI drug candidate DPC 963.

A series of isoxazolidines has been synthesized as mimetics of the RGD sequence and was evaluated as antagonists of the platelet glycoprotein IIb/IIIa receptor. These compounds were shown to be highly potent GPIIb/IIIa antagonists, exhibiting submicromolar potencies.

Early researchers studying the condensation product of carbonyl compounds with N-substituted hydroxylamines elected to coin the term “nitrone” as a combination of the words “nitrogen” and “ketone.” This was done to emphasize the parallel between this newly discovered functionality and the already rich chemistry of the carbonyl group. For example, nitrones are capable of reacting with carbanions of various types, a consequence of the iminium species embedded in the nitrone that renders the functionality susceptible to nucleophilic attack. Thus C-phenyl-N-methylnitrone undergoes a Reformatsky reaction with ethyl bromoacetate in complete analogy with benzaldehyde. The intermediate zinc alkoxide cyclizes to 2-methyl-3-phenylisoxazolidin-5-one, a type of compound that can also be prepared by the related nucleophilic addition of dialkyl malonates to nitrones. This chapter deals with a unique property of nitrones not shared by the corresponding carbonyl compounds, namely, a marked ability to undergo a [3 + 2] cycloaddition reaction in the presence of a dipolarophile. The reactions of nitrones with substituted olefins, both intermolecular and intramolecular are addressed. This process yields isoxazolidines directly, affording products related to those obtained in the Reformatsky reaction but arising by a different reaction mode. The intent of the review presented in this chapter is to provide a thorough understanding of the nitrone–olefin [3 + 2] cycloaddition reaction and to illustrate its power by describing some significant applications to complex synthetic problems. Various aspects have been reviewed. This documentation of the nitrone–olefin cycloaddition reaction begins with the preparation and stability of the nitrone component and is followed by mechanistic considerations. A presentation of the dipolarophile syntheses is beyond the scope of this chapter; however, the tabular survey provides leading references to specific examples. The important concepts of regio- and stereo-selectivities are introduced next. Since the general rules of regiochemistry that apply in the intermolecular version of the reaction are often reversed in the intramolecular version, the latter are dealt with separately. Finally, important applications to the total synthesis of natural products are presented. The versatile utility of the nitrone–olefin cycloaddition reaction in the synthesis of natural products has been the major driving force in the development of this long-neglected chemistry. An in-depth understanding of the key transformations of the isoxazolidines afforded by the reaction will place this chemistry firmly within the arsenal of organic reactions. Keywords: cycloaddition reactions; [3 + 2] reaction; nitrone; olefins; nitrone stability; mechanism; regioselectivity; intermolecular reaction; intramolecular reaction; C-alkenylnitrones; N-alkenylnitrones; natural products; alkaloids; biotin; aldehyde-derived nitrones; ketone-derived nitrones; endocyclic nitrones; exocyclic nitrones; amino glycosides; adaline; nitrogen-free systems; experimental procedures